Is the gut important in multiple joint osteoarthritis? A multimodal investigation in humans and pet dogs

项目摘要 这项工作的中心假设是，增加肠道通透性（IP），无论是直接，或通过 相关的合并症，促进多关节骨关节炎（MJOA）的发展和恶化。 多关节骨关节炎（MJOA;指的是在一个人的一个以上的关节部位OA）是常见的 但被当做替补MJOA是进行性的，随着全身OA负担的增加，相关的疼痛和 残疾增加，治疗不太成功。尽管MJOA具有重大的社会影响， OA研究仍然集中在个体关节上。迫切需要了解 促进MJOA的进展和恶化。为了验证我们的假设，我们的团队有一个大的， 人类患者的纵向队列，以及在宠物中唯一获得天然存在的MJOA模型 狗目前还没有MJOA的啮齿动物模型，但患有自然发生的MJOA的狗也有类似的疾病 与人类相比，这些表现的进展更快，使宠物狗成为理想的模型， 探索MJOA的潜在机制和潜在的治疗方法。我们已经证明， 介质与OA的总体负担有关;这些和其他风险因素可能至少部分来自 肠道微生物组通过增加的肠道通透性（IP;“漏肠”）。我们有证据表明 脂多糖（LPS）和LPS结合蛋白（LBP），反映IP增加和暴露于 微生物制品），促进OA。此外，人的血清LPS（和狗的血清LBP）是阳性的。 与受MJOA影响的关节数量相关。为了进一步阐明IP作为一种机制的作用， MJOA，拟议的工作将利用人类和狗的研究：JoCoOA，一个纵向队列， 4000名45岁及以上的黑人和白色男性和女性;约翰斯顿县健康研究（JoCoHS）， 积极入组队列（2019年-，n~2000），包括年轻（35-70岁）和西班牙裔个体;以及 在宠物犬中容易获得的天然存在的MJOA队列。所有三个队列的数据将用于 实现以下三个目标。在目标1中，我们将确定改变的IP， 全身性炎症，以及人和宠物犬的影像学和症状性MJOA。目标2将允许 鉴定预测MJOA发展和恶化的生物标志物并确定纵向 与JoCoOA参与者和犬的全身炎症标志物和IP的相关性。在目标3中， 我们将测试益生元对IP，微生物组和MJOA症状的影响，随机选择70只狗， MJOA（来自目标1）接受低聚果糖补充剂或安慰剂3个月，随后 炎症和IP的生物标志物的重新表征。这些研究都将证实 IP和MJOA增加之间的关系，并明确定义预测发展和恶化的生物标志物 MJOA，为机制研究奠定基础，以了解增加IP如何促进MJOA， 确定治疗靶点，以及提供手段来确定处于危险中的个体以进行先发制人的管理。

Project Summary The central hypothesis of this work is that increased intestinal permeability (IP), either directly, or via related comorbidities, promotes the development and worsening of multi-joint osteoarthritis (MJOA). Multiple joint osteoarthritis (MJOA; referring to OA in more than one joint site within an individual) is common but understudied. MJOA is progressive, and as whole-body burden of OA increases, associated pain and disability increases, and treatments are less successful. Despite the significant societal impact of MJOA, most OA research remains focused on individual joints. There is an urgent need to understand the factors that promote progression and worsening of MJOA. To address our hypothesis, our group has access to a large, longitudinal cohort of human patients, and, uniquely, access to the naturally occurring MJOA model in pet dogs. There are no rodent models of MJOA, but dogs with naturally occurring MJOA have similar disease manifestations with more rapid progression compared with humans, making pet dogs an ideal model in which to explore underlying mechanisms of MJOA and potential therapies. We have shown that inflammatory mediators are related to overall burden of OA; these and other risk factors may at least partly derive from the gut microbiome via increased intestinal permeability (IP; “leaky gut”). We have evidence that lipopolysaccharide (LPS) and LPS-binding protein (LBP, reflecting increased IP and increased exposure to microbial products), promote OA. Additionally, serum LPS in humans (and serum LBP in dogs) is positively associated with the number of joints affected by MJOA. To further elucidate the role of IP as a mechanism in MJOA, the proposed work will leverage human and dog studies: The JoCoOA, a longitudinal cohort of over 4000 Black and White men and women aged 45 and older; The Johnston County Health Study (JoCoHS), an actively enrolling cohort (2019-, n~2000) including younger (35-70 years) and Hispanic individuals; and a large cohort of readily accessible naturally occurring MJOA in pet dogs. Data from all three cohorts will be used to address the following three aims. In Aim 1, we will determine cross-sectional associations between altered IP, systemic inflammation, and radiographic and symptomatic MJOA in humans and pet dogs. Aim 2 will allow identification of biomarkers predictive of development and worsening of MJOA and determine longitudinal associations with markers of systemic inflammation and IP among JoCoOA participants and dogs. In Aim 3, we will test the effects of a prebiotic on IP, the microbiome and MJOA symptoms by randomizing 70 dogs with MJOA (from Aim 1) to receive either a fructooligosaccharide supplement or placebo for 3 months followed by re-characterization of biomarkers of inflammation and IP. These studies will both verify the association between increased IP and MJOA and robustly define biomarkers predictive of development and worsening MJOA, laying the groundwork for mechanistic studies to understand how increased IP promotes MJOA and to identify therapeutic targets, as well as provide means to identify at-risk individuals for preemptive management.